dbSNP rs772126322: RAC3:p.Pro87Gln (chr17-82032981-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_005052.3(RAC3):c.260C>A(p.Pro87Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P87L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAC3
NM_005052.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.96

Publications

0 publications found

Variant links:

Genes affected

RAC3 (HGNC:9803): (Rac family small GTPase 3) The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

RAC3 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with structural brain anomalies and dysmorphic facies
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

RAC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a chain Ras-related C3 botulinum toxin substrate 3 (size 188) in uniprot entity RAC3_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_005052.3

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005052.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAC3	NM_005052.3	MANE Select	c.260C>A	p.Pro87Gln	missense	Exon 4 of 6	NP_005043.1	P60763
	RAC3	NM_001316307.2		c.260C>A	p.Pro87Gln	missense	Exon 4 of 6	NP_001303236.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAC3	ENST00000306897.9	TSL:1 MANE Select	c.260C>A	p.Pro87Gln	missense	Exon 4 of 6	ENSP00000304283.4	P60763
RAC3	ENST00000924839.1		c.539C>A	p.Pro180Gln	missense	Exon 4 of 6	ENSP00000594898.1
RAC3	ENST00000924841.1		c.260C>A	p.Pro87Gln	missense	Exon 4 of 6	ENSP00000594900.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111944

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.095

MutationAssessor

Benign

1.7

PhyloP100

6.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.2

REVEL

Uncertain

0.61

Sift

Uncertain

0.016

Sift4G

Uncertain

0.029

Polyphen

0.65

Vest4

0.85

MutPred

0.49

Gain of catalytic residue at P87 (P = 0.0107)

MVP

0.91

MPC

1.5

ClinPred

0.99

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.54

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over